NM_015665.6(AAAS):c.1066_1067del (p.Leu356fs) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000255286.36

Allele description [Variation Report for NM_015665.6(AAAS):c.1066_1067del (p.Leu356fs)]

NM_015665.6(AAAS):c.1066_1067del (p.Leu356fs)

Gene:

AAAS:aladin WD repeat nucleoporin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

12q13.13

Genomic location:

Preferred name:

NM_015665.6(AAAS):c.1066_1067del (p.Leu356fs)

Other names:

p.Leu356Valfs*8

HGVS:

NC_000012.12:g.53308745_53308746del
NG_016775.1:g.17883_17884del
NM_001173466.2:c.967_968del
NM_015665.6:c.1066_1067delMANE SELECT
NP_001166937.1:p.Leu323fs
NP_056480.1:p.Leu356fs
NC_000012.11:g.53702529_53702530del
NM_015665.5:c.1066_1067del
NM_015665.5:c.1066_1067delCT

Protein change:

L323fs

Links:

dbSNP: rs763216820

NCBI 1000 Genomes Browser:

rs763216820

Molecular consequence:

NM_001173466.2:c.967_968del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_015665.6:c.1066_1067del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000321307	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 5, 2023)	germline	clinical testing	Citation Link,
SCV001249017	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Nov 1, 2023)	germline	clinical testing	Citation Link,
SCV003441104	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11159947, 12429595, 29255950, 32185032, 28492532
SCV004227250	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 12, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12429595, 29255950, 31589614, 32185032, 32938577, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene.

Handschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A.

Hum Mol Genet. 2001 Feb 1;10(3):283-90.

PubMed [citation]

PMID:: 11159947

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (8)

Details of each submission

From GeneDx, SCV000321307.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15666842, 32938577, 12429595, 32185032, 31589614, 29255950)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001249017.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

Description

AAAS: PVS1, PM2, PM3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003441104.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Leu356Valfs*8) in the AAAS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AAAS are known to be pathogenic (PMID: 11159947). This variant is present in population databases (rs763216820, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with achalasia-addisonianism-alacrimia syndrome (PMID: 12429595, 29255950, 32185032). ClinVar contains an entry for this variant (Variation ID: 264992). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV004227250.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

PP4, PM2, PS4_moderate, PVS1

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Nov 10, 2024

ClinVar

Relating variation to medicine